Toll-like Receptors (TLRs) are a family of pattern recognition receptors involved in the initiation of the immune response, allowing TLR-expressing cells of the immune system to directly recognize pathogens. TLR ligands can dramatically modulate dendritic cell function, but also the function of B cells, suggesting that stimulation through TLRs can directly modulate effector cells of the innate and adaptive immune system. Recently, it has been shown that TLRs are expressed on T cells, but only limited data are available on their role in directly modulating T cell activation and antigen-specific T cell function. Furthermore, little is known about the potential of HIV-1 to serve as a TLR ligand. Only two recent publications have demonstrated for the first time that a U-rich ssRNA sequence derived from HIV-1 LTR can serve as a TLR7/8 ligand, while additional components of HIV-1 have the potential to serve as TLR ligands, such as additional U-rich ssRNA sequences (TLR7/8), CpG-rich dsDNA generated during the viral life cycle (TLR9) and viral glycoproteins (TLR4). Detailed studies in this novel, evolving field of TLR-mediated modulation of T cell immunity are needed to begin to understand the role of TLRs, and their ligands, in HIV-1 infection. The underlying hypothesis of this proposal is that components of HIV-1 serve as TLR ligands and that HIV-1 is directly modulating T cell activation and antigen-specific T cell function through TLRs. The following specific aims will be addressed: (1) Characterization of the direct modulation of antigen-specific T cell function by TLR ligands; (2) Determination of the direct impact of HIV-1-derived TLR ligands on CD4+ T cell activation and HIV-1 replication. These innovative studies on the modulation of T cell function by TLR ligands are important for a better understanding of HIV-1 pathogenesis. Activating TLR ligands may play a crucial role in enhancing HIV-1-specific T cell immunity early in infection or as adjuvants in HIV-1 vaccines. In contrast, TLR antagonists may be able to block TLR-induced CD4+ T cell activation that facilitates viral replication in chronic infection. A better understanding of the mechanisms by which TLR ligands, including components of HIV-1, modulate T cell function will open up new avenues for the design of immunotherapeutic interventions and a rational use of adjuvants in the design of HIV-1 vaccines. [unreadable] [unreadable] [unreadable] [unreadable]